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‘one of the most important aging discoveries ever’

The science news circuits have been buzzing about Jan van Deursen’s recent paper, in which mice stayed younger, longer when their senescent cells were removed. They’re right to call this technology a game changer for anti-aging medicine. They’re wrong to say this is new—in fact, the recent paper advances only incrementally over van Deursen’s stunning results from 2011. But what they don’t explain very well is that so far this technology only works for specially-prepared mice. The mice are genetically engineered (before birth) to make their senescent cells vulnerable to a trigger that can be administered later, when they are old. We don’t yet have a way to selectively kill senescent cells in a natural mouse, or a natural human.

As we get older, a tiny minority (~1 in 10,000) of cells becomes senescent, usually through telomere shortening that goes so far as to compromise the integrity of the chromosomes. The number of cells is small, but they do outsized damage, by secreting signals into the surrounding region and even into the body as a whole that turn on inflammaging, which is one of the primary modes by which the body destroys itself. Chronic, systemic inflammation is linked to all the diseases of old age, especially arthritis, cancer, arterial diseases and Alzheimer’s.

The original paper from 2011 reported on a novel idea to test the hypothesis that getting rid of this tiny number of cells could have a positive impact on the whole body. The experiment required genetically engineered mice. That means their genes were modified in the egg stage, when the incipient mouse is still a single cell, and there’s only one set of genes to modify. Mice could be prepared in such a way that a particular gene called p16 was associated with an added gene that made the cells extremely vulnerable to a drug that wouldn’t otherwise have damaged them. This was done because senescent cells express p16, while normal cells don’t. So administration of the drug would kill just the senescent cells, while leaving normal cells alone.

The results of the experiment were dramatic. Animals that had their senescent cells removed lived 20-25% longer, and were healthier and more active at an age when other mice were in steep decline. In the recent paper, life extension was bumped up marginally to 24-27%.

From my perspective as theorist, I take this as confirmation of the idea that aging is part of the developmental program, not an unavoidable side-effect or “accumulated damage” as standard thinking allows.

The body is assassinated by signaling, not by damage.

Much of the signaling comes from a tiny minority of cells that the body could eliminate, but doesn’t.

And furthermore, there is no need for this minority to become senescent in the first place. They become senescent for want of telomerase, despite the fact that every cell in the body includes the telomerase (TERT) gene, and has the potential to produce telomerase, if it were instructed to do so. (There are many species that DO produce telomerase through their lifetimes, including mice, pigs, and cows.)

Most scientists have yet to assimilate this paradigm shift, and the popular press glosses over it with glib quotes.

This seems perverse, but there’s method to the body’s madness. Cells undergo senescence because they accumulate damage that could potentially lead to cancer, and the molecules they secrete prompt the immune system to come over and clear them. “It’s a very potent anti-cancer mechanism,” says Baker. But as we get older, the immune system falters, and senescent cells accumulate. Now, the molecules they secrete become problems rather than solutions.

Even then, senescent cells have benefits. Last year, Campisi showed that these cells help to heal wounds. And sure enough, Baker and van Deursen found that their mice heal more slowly after such cells were removed. [quote from TheAtlantic]

But (1) the cancer hypothesis has been abandonned even by its principal proponent, Judith Campisi. Senescent cells cause a net increase in cancer deaths. And (2) the idea that secretions from senescent cells may marginally increase wound healing efficiency cannot explain their evolutionary provenance if the small good is outweighed by a larger harm. The net result is that they kill us. (I wrote a related column last year.)

The Future

This technology holds up the possibility of a quick avenue toward life extension in humans that could be delivered in a treatment starting in middle age or even later. But promising as this idea is, it remains an idea and not a treatment that can be tested. Up until now, it only works in genetically engineered animals, and not in natural mice or you or me. What we need is a medication that will kill senescent cells while leaving normal cells undamaged. This is akin to the idea of chemotherapy, but perhaps somewhat easier because we have already identified a single genetic marker (p16) to identify the cells we want to kill, and because the cells are not proliferating and mutating as they are in a cancer patient. Nevertheless, there is a substantial challenge in finding the medication that can kill almost all senescent cells while leaving almost all other cells undamaged.

The word for such an agent is senolytic. Last year, two effective senolytic agents were reported: quercetin, a common botanical extract, and Dasanatib, a chemo drug [my blog post from last spring, including reference]. Though they prove the principle, they don’t distinguish senescent cells efficiently enough to offer an attractive therapy.

Some promising anti-aging technologies are being ignored by researchers and pharmaceutical companies, but this isn’t one of them. The good news is that there is a race on to test senolytic agents, with at least half a dozen labs competing to find powerful and non-toxic senolytic agents. Oisin Biotech is a start-up with a liposomal technology. Van Deursen and Campisi have their own for-profit spinoff, called Unity Biotechnology. This is now a problem of synthetic chemistry and testing, and we should know within a year or two if they are finding success.

90 thoughts on “‘one of the most important aging discoveries ever’”

I had the exact same question in mind with the 4-5 days prolonged fasting (de Longo). It would be nice to see whether the life extension effects of DR, PF are additive to the SASP clearance treatment, or they are on essentially the same pathway.

sorry. DR= dietary restriction of about 10-40% of ad libitum feed. this is the only intervention proven to cause lifespan/healthspan across many species.
PF prolonged or periodic fasting. proposed by Valter Longo. Its basically 3-4 days of water fasting every 2-4 weeks. It is not dietary restriction, because total calory intake in lifetime is not reduced. However according to Longo’s papers it can mimic DR with relatively short suffering. However PF is not as deeply researched as DR.
Many readers of this blog follow PF, Josh wrote a couple of entries on PF.

Thanks Gator, yes very familiar with Longo’s work just didn’t know abbreviations…I have been doing 16 hour fasts 5 out of 7 days for last year and aside from possible senescence benefits I feel fantastic. Also playing with beta-hydroxybutyrate to enhance ketone production after the fast. I’m charting interesting changes in workouts, respiration quotients, strength, and muscle growth, which at a long tall 61 is unusual. 🙂

Thanks for the link to the original paper. Actually reading the paper makes me believe that the results are better than face value. AP treated non transgenic mice dies sooner then non treated transgenic mice, so the AP might itself has a toxic effect that is countered by SASP clearance alongside the effect of SASP cells.
Also worthy to note that these results were achieved without SASP clearance in liver. And SASP clearance was rather muted in heart and kidney as well.

It may be that we humans actually get a longer than the 25% or so life extension they get. The reason why I think that is because we humans are far more likely to be bottlenecked by senescent cells than any species of mice.

I’d like to see a study of cell senescence on some animals believed to not age, such as the Aldabra giant tortoise, and the Rougheye rockfish.

In Hydra, the FoXO gene has been found to be the cause of their immortality, but that is a relatively simple life form, which is why I want the tortoise and the rockfish reviewed.

FOXO3 has been known to be associated with longevity in human centenarians.

Results of research have been favorable enough for me to start using quercetin (as EMIQ) about once every ten days. Back of the envelop figuring lead to chose that frequency to catch newly emerging cells of senescent phenotype as they clock out of the earlier stages of development.

EMIQ is a product that can deliver high serum concentrations with oral use. It seems rational to use it in a pulsatile manner.

Having an effective senolytic agent in an over-the-counter dietary supplement and requiring use only perhaps three times a month is a great change from daily use, trying to sustain effective serum levels.

The means for an effective home-based senolytic therapy seems to be within the reach of average consumers.

I’m glad you’re doing this. I’m involved in an experiment doing something similar with mice, and hearing your experience will add to what we learn from the mice.
I wouldn’t say that “an effective home-based senolytic therapy…”, because we won’t know whether it’s effective or not until you and some more brave people like you report your results.

Is there an easy blood marker for senescent cell death? (E.g. p16 in the blood?) It would be nice to be able to tell what doses of putative senolytics actually work…

This is a very exciting field, as others have pointed out humans should have a lot more senescent cells than “old” mice… mice don’t even use telomere shortening as a cancer-control mechanism, the control cells for our TRAP assays are just normal mouse cells…. old humans on the other hand have lots of telomere-deficient cells.

I’m guessing (and staking my precious metabolism on it!) that the pulsitile dosing regimen is key to senolytic effects. If x cells go senescent a day, and are (theoretically) bumped off buy circulating quercetin the effect though cumulative would be progressive and liable to side-effects from prolonged use of quercetin. Q is not famous for such, but might happen. MMmm-k.

Rather like curcumin it’s absorption and bioavailability that are limits to the compounds’ therapeutic potential. With EMIQ one stands a good chance of achieving an effective serum level, and in isolated doses, to clean house so to speak.

“EMIQ or Enzymatically Modified Isoquercitrin is prepared by using a natural enzyme process that attaches polysaccharides to convert quercetin, which has poor bioavailability, into a soluble form (Alpha-Glycosyl Isoquercitrin). EMIQ provides the benefits of quercetin with high absorption and superior bioavailability. According to pharmacokinetic data, the absorption of EMIQ is up to 40 times greater (Cmax) and 15 times greater (AUC) than that of quercetin and reaches peak levels in the bloodstream in just 15 minutes. An antioxidant for the maintenance of good health.

Enzymatically modified isoquercitrin (EMIQ) is a highly bioavailable form of quercetin – a flavonoid that exerts significant anti-allergy effects. EMIQ is manufactured through natural enzymatic process that attaches glucose chains (glycosides) to the quercetin molecule. The result of this modification is that the quercetin is provided in a water-soluble form thereby greatly enhancing its bioavailability. In the digestive process the glycoside portion is cleaved, liberating the quercetin, and as a result EMIQ greatly increases quercetin levels in the blood compared to the ingestion of quercetin or its related compound rutin. Blood levels of quercetin are more than 40 times greater with EMIQ compared to an equal amount of quercetin.

EMIQ has been found to be safe in many toxicity studies and has been self-affirmed as Generally Recognized as Safe (GRAS) for use in specific foods in the US and as an antioxidant. Natural Factors Bioactive Quercetin EMIQ contains no GMOs, artificial colours, preservatives or sweeteners, fish, shellfish or animal products, and is suitable for vegetarians/vegans.

Yes – in fact, mouse life span was shortened by quercetin in Spindler’s experiment, and perhaps one more. If quercetin can be used to lengthen mouse life span, it will have to be in high, intermittent doses.

Josh, What’s the evidence that most senescent cells become that way for want of telomerase? Various carcinogenic insults (e.g. ionizing radiation) can initiate senescence, as can strong mitogenic signals, HDAC inhibition, oxidative stress, or loss of the Pten tumor suppressor. Telomere depletion is a problem in culture, where cells are passaged sufficient to run up against the Hayflick limit, but most cells in vivo do not reach the Hayflick limit. You mentioned that mice produce telomerase throughout their lives, but mice certainly develop senescent cells.

Not all mouse cells produce sufficient telomerase to keep going according to some papers I have there are a number of mouse stem cells that do not keep pace. Mice are also very prone to Oxidative stress which is another major reason why they suffer telomere dysfunction.

Cellular senescence is a program activated by normal cells in response to various types of stress. These include telomere uncapping, DNA damage, oxidative stress, oncogene activity and others. Senescence can occur following a period of cellular proliferation or in a rapid manner in response to acute stress. Once cells have entered senescence, they cease to divide and undergo a series of dramatic morphologic and metabolic changes. Cellular senescence is thought to play an important role in tumor suppression and to contribute to organismal aging, but a detailed description of its physiologic occurrence in vivo is lacking. Recent studies have provided important insights regarding the manner by which different stresses and stimuli activate the signaling pathways leading to senescence. These studies reveal that a population of growing cells may suffer from a combination of different physiologic stresses acting simultaneously. The signaling pathways activated by these stresses are funneled to the p53 and Rb proteins, whose combined levels of activity determine whether cells enter senescence. Here we review recent advances in our understanding of the stimuli that trigger senescence, the molecular pathways activated by these stimuli, and the manner by which these signals determine the entry of a population of cells into senescence.http://www.sciencedirect.com/science/article/pii/S1357272504003875

I have run TRFs on cells from human patients of different ages… there is huge variance, but the correlation between age and shorter average telomere length is clear. There are many tissues where cell turnover is quite high, and one would expect those tissues to contain many senescent cells. (In a mouse that’s less than two years old [because lab mice are inbred and not much like real mice, which live at least 4, cf Austad], and has active telomerase in every cell, that’s another question… I’d be surprised if telomeres are a factor at all.)

If degradation of the immune system is to blame for the reduced clearance of the senescent cells, perhaps intermittent rev-ups of the immune system (with “young” immune cells) would act as a senolytic?

One particular immune stimulant excited my attention back in the ‘eighties: levamisole. Available at the livestock medicine section of the local feedstore.

As I understood it then (and haven’t given it a thought since) that following a dose macrophages go on a killing frenzy. They gobble up every slightly deformed membrane protein, then gobble up the cell it damaged doing that, and the whole population of macrophages crashes…death by gluttony.

One is left relatively immune exhausted for a week or so until stem cells divide enough to replace the newly departed. So caution is in order with exposure to infectious patients. I was in a very clean pre-surgical service so this wasn’t a problem.

Levamisole has a rather unique and intriguing side effect… at random unpredictable moments one is overcome with a olfactory hallucination. I’d never heard of ’em ’till Lev delivered a number each day of treatment which I limited to three consecutive days q monthly max.)

I’m my case, the overwhelming odor was of bleach. I like bleach smell…in hospital it means someones been cleaning! Not as common as you’d hope, alas.

Now, macrophages do their lethal work with exocytosed cytotoxins… are they rich in Cl- ions I wonder? What the ‘hallucination’ may have been was my nose ‘turned inwards’ and smelling my own blood! Awash in macrophage cytokines. Awesome! as a theory.

For cell clearance Levamisole is awesomely powerful, cheap, easily available, but from what I read (back in the day), rather indiscriminate. I don’t know if it releases ‘programming’ to macrophages as to what particular cells it’s going to go gobble up.

Might gobble up articular cartilage…who knows?

I think Levamisole stands another look.

Its use for senescent cell destruction (presuming it actually does trigger that) could be patent-able. It clocked off patent as a livestock dewormer decades ago. It may be that it’s not patented at all for human use. In that case, the horrible expense of clinical trials would be required.

gcmaf is the most potent macrophages activator (it is indeed called macrophage activating factor) and i got few researchers interested in the possibility of gcmaf activated macrophages to clear senescence cells.theoretically it can clear senescence cells, hope this can lead to some mice studies as well.for now i ll be the one trying it combo with ta65 and nicotinamide ribosidehttp://joshmitteldorf.scienceblog.com/2015/04/22/telomerase-does-not-cause-cancer/

“One particular immune stimulant excited my attention back in the ‘eighties: levamisole. Available at the livestock medicine section of the local feedstore. As I understood it then (and haven’t given it a thought since) that following a dose macrophages go on a killing frenzy.”

Lev has graduated from a wormer to a cut for coke. So it goes.
Come pension day I’m getting a single tablet of VERMOX, another wormer, to mow down the lingering enemies within.
I’ve done about 60 cycles of EMIQ, Theracurmin, gingerol, piperine to take out senescent cells, so I’m ready for telomere extension on the remaining population: EPITHALON and THYMOSIN BETA-4.

oh, no, I don’t know how to document any clearance. I would guess that tissue culture techniques would need to be employed. Not do-able at my home.
Do you know of how it might be done?
Thanks, Marco.
J.

the gcmaf researcher said gcmaf activated macrophages do clear senescence cells but as we age they probably lose this functionality.
my own documented story of reverasl advanced compensated micronodular cirrhosis proves (no other possible ways this happened) gcmaf acted this way.fibrosis reversals happened by few months in 2011 (i am now almost 47yo) and same happened 5 years later with the nodules.the nodules cleared after 1 year of interferon+gcmaf treatment, i injected subcutaneously both on liver.nodules enlarged from 3mm to about 7-9mm and then 6months later no trace of them

from their research: “Moreover, in liver fibrosis, the precursor pathology for cirrhosis, I have shown that the main fibrogenic cell type in the liver, activated hepatic stellate cells, become senescent and are cleared by the NK cells thus limiting fibrosis progression and facilitating its reversion”

i dont post the research about interferon clearing senescence cells, this is kind of hell heavy sides effects treatment, if i go back i dont know if i would use it.
so if we suppose gcmaf is able to activate macrophages to clear senescence cells at some degree, will telomerase activators be potent enough to keep immune system in good shape if used before aging lets say before 50yo?i think this could be a good cycle, gcmaf has no sides effects on its own if we use a cream formulation instead of injection (its a blood product so injecting can have theoretic possibility of infection transmission) and its a natural protein we all have to live.did you find any proof EMIQ works?

With recent discussion of enhancing telomerase to delay a cells entry into senescence, I wonder if delaying it is ultimately a good strategy for organismal longevity.
If cells remain in the reproductive stages there is longer time for mutation. They will _all_ eventually clock out into senescence… is blocking the exits from the cell cycle a good idea?
Triggering rather than suppressing apoptosis would seem more promising a strategy. Enhancing apoptosis would in effect crowd the exits, so that doesn’t sound very promising either. They’ll all get there eventually.
Senolytics will punch their ticket when they get there.
Thoughts?

No because telomerase restores telomeres and restores a youthful phenotype via TPE. It is a bad idea for too many cells to enter apoptosis at once, in fact Reason at fight aging and Oisin Biotech have both mentioned this recently.

An course of senolytics followed by telomerase would remove and restore the body so it is more about calibrating that removal and replacement than simply one extreme or the other.

Also remember that restoring cellular phenotype to youthful levels would boost macrophages which would in theory improve senescent cell removal too.

Regards Navitoclax the MMTP project considered this candidate drug but opted for D&Q in this first phase. We may try Navitoclax but we have other options including on the horizon that are potentially far more effective.

I share your doubts. I think telomeres are the red herring in the ageing field.
Its probably very easy in the lab to exhaust telomeres in a cell culture therefore it draws a lot of attention. But does telomere length have any impact on real living organisms?
We know that mice arent short of telomeres at all, yet at the age of 12 months they start to produce senescent cells in an accelerating fashion. In fact I just followed up the subject article. How do they differentiate between senescent vs normal cells? p16 expression by the INK4a/ARF locus. How is p16/INK4a expression regulated?https://www.researchgate.net/profile/David_Murray15/publication/230743547_Role_of_p16INK4A_in_Replicative_Senescence_and_DNA_Damage-Induced_Premature_Senescence_in_p53-Deficient_Human_Cells/links/53fb3fd90cf27c365cf08b38.pdf
There are couple of ways:
– p38 upregulates vs
-AUF1
-T box proteins
– polycomb group proteins
– histone deacetylases
– transcription regulators E2F1, cMyc
– p53 (DDR)
all downregulates
p16INK4a seems like coiled spring that can be released by many triggers. Of these polycomb group and histone deacetylases are the most interesting as they are correlated with the developmental program and the epigenetic clock of ageing.
If I had some time I would certainly look up the age related DNA methylation differential around the p16INK4a locus.

Remarkably, though, continuous
clearance of senescent cells for over 9 months did not have overt
adverse effects, but rather enhanced health span and function, at
least in progeroid mice housed in an animal facility

(sorry no time for citations) but this seems to support my caution about using epithalon to lengthen telomeres until 30 or so cycles of (hypothetical) SASP cells with q 10 day EMIQ doses.

Jesus Christi, Gabor, I think I’m joining you on this ‘beam’. I think this way may lay our salvation.

Promote longevity _after_culling the population of old foggie cells.
Am I reading you and your materials correctly?

You should also read Randos telomeres – P53 – Pcg-1a aging axis for further understanding on the role they play. It’s also not just telomeres but telomerase interacting with wnt that is vital for stem cell function and mobility.

Far from being a red herring they are vitally important, however there are ways to fix the underlying damage to revert their dysfunction eg, AGE cleaving and reduction of TGF-beta1 levels for one.

Hi Steve,
My doubts:
telomere length is not a good predictor of chronological age. DNA methylation is a good predictor, even in non dividing cells (like neurons).
Mouse telomeres at old age are still longer than human telomeres of newborns.
Variation of telomere length within age groups is almost as large as variation across age groups.
Mouse stem cells maintain telomere length.
Telomerase overexpression cannot significantly extend mouse lifespan.
Some of my arguments are summarized herehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742037/
Maybe long telomeres are a way of fending off DNA damage. DNA repair might not be so efficient at the end of chromosomes.

What would be really interesting to see someday is if we could somehow make a cell that has undergone cell senescence somehow undo the damage by producing telomerase and perhaps lengthen its telomeres somehow.

I’m suspecting that telomerase would just extend the lifespan of an already damage cell letting it reproduce it’s screwed up phenotype for cellular generations to follow. clearance first, extension after. just a thought. One I’m betting on.

Well, apparently a simple compound prepared in a special way can do this. EMIQ (enzymatically modified iso-quercetin) does it good. Not to all the cells that danasinib does, but I don’t need chemo. Yet. nyuk nyuk nyuk.

I think there is one other matter we need to discuss. Something is causing the production of senescent cells independent of shorter telomeres.

Do you think that Josh’s hypothesis may be right – signalling, only something is causing even cells with a very healthy length of telomeres to “go senescent”? In that case, we may not only want to re-lengthen telomeres of short cells; we also will want to shut down this mechanism somehow.

Or cellular response to inflammatory cytokines from neighboring senescent cells. A cascade effect. Not to be encouraged. They must die. The fit should be allowed to overwhelm the population. Kill first, promote lifespan later, I’m guessing.

My take on cellular senescence in healthy tissue is that it is basically controlled by chromatin quality as organisms age.
My understanding is that aging is foremost a degeneration of chromatin quality in all cells, regardless of proliferation potential and history (e.g. telomere length). DNA methylation change is the most researched. As ageing progresses the genome gets globally hypomethylated and also specific sites that had been hypomethylated before get hypermethylated. Those sites that get methylated by age are initially associated to PRC2 regulated sequences. PRC2 becomes dissociated as DNA methylation progresses thus losing regulation over the sequence. In contrast the hypomethylated sites are “random” and genomewide. All this I believe leads to significant transcriptional noise as the mask of methylation degrades on top of the genome. Sequences that are never supposed to be expressed start to have an increasing chance of expression. I believe this degrades cellular function and increases the chance of cancer.
Senescence happens because alongside random sequences p16Ink4a too becomes upregulated by PRC2 dissociation in the manner of a dead man’s switch. This means the threshold for senescent transformation lowers by ageing so more and more cells arrests themselves to avoid malignant transformation.
So I think p16INK4a expression is correlated with chromatin ageing. Its a robust safety mechanism.
I think the most exciting question is why these chromatin changes happen and how the ageing of chromatin could be stopped or turned back.
In the worst case chromatin is degraded because of oxidative stress and there is no chance to turn back the DNA methylation changes except for fertilization.

You wrote: “…there is no chance to turn back the DNA methylation changes except for fertilization.”

I’m only familiar with fertilization in the uterine sense. There’s another?

Thanks!
JH

A digression:
*methylating DNA*
In Pearson and Shaw doctrines, methylating agents were promoted a lot. They advised in some cases to supplement with methionine, then available over the counter as a urinary acidifier in order to….uh, skip that for now. Then came advice for the more expensive cysteine. The benefits of sulfhydryls were recognized, mainly for the purpose of methylating DNA. Back before video imaging of sims, then they were often visualized as yarms in woolie stockings over the genes. an image for what it’s worth.

At present I use NAC for that purpose. I get so much folic acid here in Chinatown I could bottle it. (folic good too for methyl-DNA).

well I mean, the chromatin state can be reprogremmed into a youthful state via fertilization (union of egg and sperm), cloning (nucleus transfer into oocyte) and IPS reprogramming.
the sad thing is it always happens like a big bang, a total reset to pluripotent state and chromatin age zero. never goes back a little bit and never preserves the state of existing differentiation.

. Vernalization (a Russian invention) changed frozen wheat to a different phenotype sans genetic mods. I wouldn’t expect to be able to de-vernalize back to winter wheat (vs. spring wheat). but who knows.

So descenescence shouldnt seek to protect current gene-expression by telomere extension, but simple elimination of the unfit. By enhanced apoptosis? , but to cull the cell population so ‘fresh’ stem cells overtake the tissue?

my understanding is that simple elimination of the unfit is not enough… all the cells are getting older day by day chromatinwise. The worst, the most stressed morph into senescence secretory phenotype, ok, we kill them, but the rest wont get any better by this, only that they wont get much worse.
I think in the end lab created, autologous, stress tested, genetically modified stem cells will re-populate the human body

It is possible to devernalize a plant by exposure to high temperatures subsequent to vernalization. For example, commercial onion growers store seeds at low temperatures, but devernalize them before planting, because they want the plant’s energy to go into enlarging its bulb (underground stem), not making flowers.[17]

Vernalization is the process by which prolonged exposure to cold temperatures promotes flowering. Over the past century, this process has been studied extensively at the physiological level. Recent studies have provided some insight into the molecular basis of vernalization. The rich history of vernalization research has been discussed in detail in many reviews (Chouard, 1960; Lang, 1965; Bernier et al., 1981). I will briefly summarize some highlights and classic experiments that I would like to relate to recent molecular advances.
Go to:
HISTORY OF VERNALIZATION RESEARCH

The first papers describing exposure to cold as the specific climatic aspect of winter that was necessary for flowering in some species were published in the latter half of the 19th century. However, the work of Gassner (1918) is usually cited as the first report that a wide range of plant species require cold exposure to flower (Chouard, 1960; Lang, 1965).

There are several ways to classify the vernalization responsiveness of plants. One is whether a requirement for exposure to the prolonged cold of winter to flower influences the plant’s life history. Monocarpic species senesce after flowering and setting seed. Monocarpic plants that require vernalization to flower thus typically require two seasons to complete the life cycle and are usually classified as biennials or winter annuals. The term biennial is often used for plants that have an obligate requirement for cold exposure to flower, and the term winter annual is often used for plants with a quantitative cold requirement (Lang, 1965; Figure 1A). Monocarpic species that flower in one growing season without a vernalizing cold treatment are often called summer annuals. Many polycarpic species (i.e., perennials) also require a vernalizing cold treatment to enable flowering.
Figure 1.
Figure 1.
Examples of Plants Requiring Vernalization.

The distinction between summer annuals and winter annuals or biennials is not always absolute. It is possible that genetically identical plants could behave as summer annuals in one location and as winter annuals in a different location with a different climate. Furthermore, these classifications do not imply fundamental differences in the mechanisms that control flowering. In Arabidopsis, for example, single-gene changes can convert plants without a vernalization requirement into plants that have either a quantitative or obligate requirement or vice versa; therefore, the relevant molecular differences between plants in various categories can be minor.

Many winter annuals and biennials become established in the fall, taking advantage of the cool and moist conditions optimal for their growth. The vernalization requirement of such plants prevents flowering until spring has actually arrived. Weather is often variable, so for a vernalization requirement to work as intended, plants must not only sense cold exposure but also have a mechanism to measure the duration of cold exposure. For example, if a plant is exposed to a short period of cold in the fall season, followed by a return of warm temperatures later that fall or in early winter, it is important for the plant not to perceive the brief exposure to cold and the following warm weather as spring. One mechanism to determine that spring has in fact arrived is to measure the duration of cold and to permit flowering only after a period of cold that is sufficient to ensure that winter has passed. Sensing the increasing daylengths in the spring can also play a role. In many perennial species, the release of buds from dormancy only after perception of a sufficient duration of cold exposure is, like vernalization, designed to measure the duration of a winter season. Processes that require prolonged exposure to cold, such as vernalization and the cold-induced release of bud dormancy, stand in contrast with cold acclimation—a process designed to respond to cold as rapidly as possible (Thomashow, 2001).

Within a given species, there can be variation in the extent to which vernalization affects flowering time. In some species there are varieties that require vernalization and others that do not, such as winter and spring varieties of cereals (e.g., winter wheat and spring wheat). In fact, the term vernalization comes from studies of flowering in cereals. The infamous Russian geneticist Trofim Lysenko, who studied the effect of cold on flowering, coined the term jarovization to describe what we now call vernalization. Spring cereals are called jarovoe in Russian (derived from Jar, the god of spring), and cold exposure causes a winter cereal to behave like a jarovoe (i.e., to flower rapidly). Jarovization was translated from Russian into vernalization; vernal is derived from the Latin word for spring, vernum (Chouard, 1960).

A useful definition of vernalization is provided in Chouard’s review (1960, p. 193): “the acquisition or acceleration of the ability to flower by a chilling treatment.” Two types of experiments demonstrate that this acquisition or acceleration is occurring at the shoot apex. One is to locally chill only certain parts of the plant. Another is to graft shoot tips: In most species, if a vernalized shoot tip is grafted to nonvernalized stock, it will flower, but a nonvernalized shoot tip grafted to a vernalized stock will not flower.

As noted in the above definition, cold exposure does not necessarily cause flowering but rather renders the plant competent to do so. A classic demonstration of this comes from the work of Lang and Melchers (reviewed in Lang, 1965) using biennial Hyoscyamus niger (henbane). Biennial henbane requires vernalization followed by inductive photoperiods to flower. If vernalized henbane plants are grown in noninductive photoperiods, they continue to grow vegetatively. However, if such plants are later shifted to inductive photoperiods, they flower. This shows that the vernalized plants are able to remember their prior vernalization; that is, they had acquired competence to flower but did not actually do so until the photoperiod requirement was met. Thus, vernalization establishes a cellular memory that is stable through mitotic cell divisions. The length of this memory of winter varies among plant species; in some species it is much shorter than in henbane.

I think it is reasonable to refer to the vernalization-induced, mitotically stable acquisition of the competence to flower as an epigenetic switch because it is a change, YADA YADA YADA BUDDHA BINGX2

EMIQ is a product that can deliver high serum concentrations with oral use. It seems rational to use it in a pulsatile manner.

Having an effective senolytic agent in an over-the-counter dietary supplement and requiring use only perhaps three times a month is a great change from daily use, trying to sustain effective serum levels.

The means for an effective home-based senolytic therapy seems to be within the reach of average consumers.

Newly returned from forced obscurity, Joseph is now renewing his footprint on the internet and is networking with various talents in the field of radical life extension/health enhancement, and sexual medicine.
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Soooo, how do we choose which mRNA to get from this plant?
Easy matter, now we’re talking gene transplants, eh? This is your field, Gabor?
Chose one from a plant, shotgun it into e.coli, sop up the mRNA they dribble out and feed it to an animal subject.

Broc concentrate powder is part of my well-rounded diet of supplements. I’ve held to a q10day schedule because my aim was to only do senolytic (SASP cell removal).

I’ve held off a bit too cuzza that broc & co. can have waay high nitrate levels. Usually would embrace that as a good thing, except I think it’d potentiate my cheap Chinese Cialis too much.
Get a bone, faint from massive fluid shift. You know where to.

I might monitor for that, cuz it looks like what’s really promising in there isn’t glucoinosaltes, sulphorophane, and whatall… it’s also AMAZINGLY got messenger RNA that is easily absorbable, and incorporates into yur own wee genome. Far Fuckin’ Out!

Now gotta’ figur what them mRNA is doing in there?
Plans to follow.
New to internet, really need to make a blog of my own. How?

A eugenic approach, though ill considered and implemented in the social sphere is entirely appropriate in terms of senescent cell removal. What we need are ‘cattle cars’ to load the decrepit to feed into the furnaces of our mitochondria.

Our agents will sweep up hoards of rogue “decreps” by use of targetted immune cells, both phagic and serum based. B-cells will speard bait for them in the form of antibodies. Once they glom onto the surface antigens of marked senescent cells, our shock troops descend for the slaughter.

As the bard Jim Morrison said, “Blood will be borne in the birth of a nation”

Oi oi,,,, our forces could also be modeled upon White Supremacist clans. I don’t want to go there. Drawing parallels to the SS is as far as I’ll take it today.